A drug has a narrow therapeutic index and is 95% protein bound. A co-administered drug displaces it from albumin, reducing binding to 90%. What is the expected change in free drug fraction and clinical significance?

• A Free fraction increases minimally because most drug remains protein bound at 90%
• B Free fraction doubles and directly doubles steady-state total plasma concentration
• C Protein displacement always causes clinically significant toxicity regardless of pharmacokinetic compensations
• D Free fraction doubles (from 5% to 10%), transiently increasing free drug levels; however, increased free drug also increases distribution and elimination, so steady-state free concentration may not change significantly unless elimination is also saturated ✓

Explanation

When a drug's protein binding drops from 95% to 90%, the free fraction doubles (5% to 10%). This transiently increases free (active) drug concentration, potentially causing toxicity. However, unbound drug is also more available for hepatic metabolism and renal excretion — so the apparent volume of distribution increases and clearance of free drug increases. For drugs with high extraction ratio, the increased free fraction is rapidly cleared, and new steady-state free drug concentration may not be significantly different. For drugs with low extraction ratio (capacity-limited elimination), the free fraction increase is more clinically relevant. The classic teaching of warfarin-aspirin displacement causing major bleeding has been reassessed; the interaction in practice is primarily due to COX inhibition, not displacement.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.